Lecture 2 Flashcards
What is the major tissue of elimination?
Kidneys
How much blood goes to the kidneys?
1/4
Tissue of elimination, not kidneys?
Enterohepatic Circulation
Other tissues of elimination
Sweat/saliva/lacrimation (rifampin); certain drugs contraindicated if wear contacts
Pulmonary: volatile anesthetics, EtOH
Mammary tissue: via lactation
Renal Clearance
ml/min
rate of renal excretion (mg/min)/
plasma concentration (mg/ml)
Chronic HTN associated with DM destroys the glomerular capillaries. This could mean:
Elevated Cmax &
Extend (lengthen) half-life &
Shorten onset time of drug
Why do reductions in renal blood flow and GFR increase drug toxicity?
Increases Cmax and half-life
Plasma Binding Proteins (PBP)
What are they? Which is the most common?
Reversibly bind drugs in blood stream, inactivating them because too big to leave blood vessel. Main PBP is albumin.
What are 2 main PBP
Albumin, which has a low affinity (so drug needs to be in high concentrations), is least selective, is most common
Globulin, which has high affinity (so will bind drugs in low concentrations), selective binding to sex steroids.
How is PBP a reservoir?
Drugs are bound reversibly, so when free concentration drops, can unbind from PBP. While bound, not metabolized or excreted.
How is PBP effected by disease states in liver, kidneys, diet?
Malnourishment, liver (hepatic disease decreases PBP) and kidney disease (proteinuria) cause decreased amounts of PBP, so many meds have greater free concentration which increases toxicity.
What effect does tissue deposits have?
- Serve as a reservoir for a drug.
- Alter dosing strategies. (loading/induction/priming) and maintenance.
- sites of toxicity
Where does most metabolism occur and by what?
Liver by P450 system.
Most drugs are metabolized by 3 families of CYP enzymes, CYP1, CYP2, CYP3
What 3 things affect metabolism?
- Age (old and young)
- inducers: increase metabolism by increasing CYP synthesis
- Inhibitors: Decrease metabolism by interfering with CYP synthesis.
What are the major metabolic tissues?
Liver, kidneys, GI tract, lungs, blood plasma
Where are CYPs in liver?
In ER
3 classes of Metabolic Enzymes
- Microsomal (CYPs)
- Hydrolytic (eg: pseudocholinesterase)
- Conjugation: glutathione S transferase
How do CYP enzyme inducers work?
the xenobiotic(drug inducer)==>orphan receptor==>CYP gene==>increases production of CYP enzyme (induction)==>increases metabolism==>decreases xenobiotic==>decreases orphan receptor stimulation and therefore CYP gene activation.
Conjugation Enzymes
Enzymes that conjugate a conjugation molecule (like glutathione) to a drug. The complex is inactivated and has increased water solubility, increasing its renal excretion.
Metabolic Phases
- CYP or hydrolysis
2. Conjugation
First Pass Metabolism
Where most of an oral drug is metabolized before reaching circulation.
GI tract_hepatic portal vein_liver_IVC_systemic circulation
Biotransformation
An act of metabolism
- drug inactivation
- Prodrug activation
Metabolism in drug resistance
Some cancer cells increase production of conjugation enzymes to kill anticancer drugs (increase glutathione S-transferase)
Individualized factors
Males metabolize benzos faster
What does our microbiota have to do with metabolism?
There are 100x more genes in our microbiome.
These genes affect our absorption and metabolism, like in digoxin, acetaminophen, tamoxifen, simvastatin.
Major tissues of elimination:
- Renal
- EHC (enterohepatic circulation)
- Sweat/Lacrimation/saliva
- Pulmonary
- Mammary
EHC
Drug in GI tract_hepatoportal vein_Liver_drug+bile salts_bile_small intestine_blood plasma or feces. This process occurs many times before drug is completely eliminated in feces.
What is the effect of multiple drugs in regards to PBP?
Sometimes drugs will compete for binding sites and one drug can end up with higher free fraction, causing increased intensity of response or toxicity.
